Compositions and methods of enhancing or augmenting type i ifn production

Abstract

Disclosed herein are methods and compounds of augmenting and enhancing the production of type I IFNs in vivo. In some embodiments, also disclosed herein include methods of activating and enhancing the cGAS-STING response and use of an immunogenic cell death inducer with an inhibitor of a phosphodiesterase for the treatment of cancer.

What is claimed is: 
     
         1 . A method of treating a subject having a cancer primed by an immunogenic cell death (ICD) inducer, comprising:
 administering to the subject a phosphodiesterase (PDE) inhibitor, wherein the PDE inhibitor prevents hydrolysis of 2′3′-cGAMP.   
     
     
         2 . The method of  claim 1 , wherein the PDE comprises an ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) protein. 
     
     
         3 . The method of  claim 2 , wherein the ENPP protein comprises ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP-1). 
     
     
         4 . The method of  claim 1 , wherein the PDE inhibitor is a small molecule. 
     
     
         5 . The method of  claim 1 , wherein the PDE inhibitor is a ENPP-1 inhibitor. 
     
     
         6 . The method of  claim 1 , wherein the PDE inhibitor is a reversible inhibitor, a competitive inhibitor, an allosteric inhibitor, a mixed inhibitor, or an irreversible inhibitor. 
     
     
         7 . The method of  claim 1 , wherein the PDE inhibitor comprises ARL67156, diadenosine 5′,5″-boranopolyphosphonate, adenosine 5′-(α-borano)-β,γ-methylene triphosphate, adenosine 5′-(γ-thio)-α,β-methylene triphosphate, an oxadiazole derivative, a biscoumarine derivative, reactive blue 2, suramin, a quinazoline-4-piperidine-4-ethylsulfamide derivative, a thioacetamide derivative, PSB-POM1412-(3H-imidazo[4,5-b]pyridin-2-ylthio)-N-(3,4-dimethoxyphenyl)acetamide or a derivative, analog, or salt thereof; 2-(6-Amino-9H-purin-8-ylthio)-N-(3,4-dimethoxyphenyl)-acetamide, or a salt thereof; N-(3,4-Dimethoxyphenyl)-2-(5-methoxy-3H-imidazo[4,5-b]-pyridin-2-ylthio)acetamide or a salt thereof; 2-(1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl sulfamide or a salt thereof; ((1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl)methyl)sulfamide or a salt thereof; or SK4A (SAT0037) or a derivative or salt thereof. 
     
     
         8 . The method of  claim 1 , wherein the PDE inhibitor comprises Compound 1, Compound 2, Compound 3, or a derivative, analog, or salt thereof. 
     
     
         9 . The method of  claim 1 , wherein the cancer is a solid tumor comprising breast cancer, lung cancer or glioblastoma, or a hematologic malignancy. 
     
     
         10 . The method of  claim 1 , wherein the cancer is a hematologic malignancy comprising a leukemia, a lymphoma or a myeloma. 
     
     
         11 . The method of  claim 1 , wherein the immunogenic cell death (ICD) inducer comprises radiation, a small molecule compound or a biologic, or a chemotherapeutic agent. 
     
     
         12 . The method of  claim 1 , wherein the PDE inhibitor is administered continuously, at predetermined time intervals or intermittently for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days. 
     
     
         13 . The method of  claim 1 , wherein the PDE inhibitor is administered to the subject at a therapeutically effective amount. 
     
     
         14 . The method of  claim 13 , wherein the therapeutically effective amount of the PDE inhibitor selectively inhibits hydrolysis of 2′3′-cGAMP. 
     
     
         15 . The method of  claim 13 , wherein the therapeutically effective amount of the PDE inhibitor reduces ATP hydrolysis in PDE by less than 50%, less than 40%, less than 30%, less than 20%, or by less than 10% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. 
     
     
         16 . A method of enhancing type I interferon (IFN) production in a subject in need thereof, comprising:
 administering to the subject a pharmaceutical composition comprising:
 i) an inhibitor of a 2′3′-cGAMP degradation polypeptide to block the hydrolysis of 2′3′-cGAMP; and 
 ii) a pharmaceutically acceptable excipient; 
   wherein the presence of 2′3′-cGAMP activates the STING pathway, thereby enhancing the production of type I interferons.   
     
     
         17 . The method of  claim 16 , wherein the production of IFNs is localized in a tumor microenvironment. 
     
     
         18 . The method of  claim 16 , wherein the 2′3′-cGAMP degradation polypeptide is a phosphodiesterase (PDE). 
     
     
         19 . The method of  claim 16 , wherein the 2′3′-cGAMP degradation polypeptide is an ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) protein. 
     
     
         20 . The method of  claim 16 , wherein the 2′3′-cGAMP degradation polypeptide is ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP-1). 
     
     
         21 . The method of  claim 16 , wherein the cell has an elevated expression of PDE. 
     
     
         22 . The method of  claim 16 , wherein the cell has an elevated population of cytosolic DNA generated by an ICD-mediated event. 
     
     
         23 . The method of  claim 16 , wherein the inhibitor is a PDE inhibitor. 
     
     
         24 . The method of  claim 23 , wherein the PDE inhibitor is a small molecule. 
     
     
         25 . The method of any one of  claims 23  or  24 , wherein the PDE inhibitor is an ENPP-1 inhibitor. 
     
     
         26 . The method of any one of the  claims 16  or  23 - 25 , wherein the PDE inhibitor is a reversible inhibitor, a competitive inhibitor, an allosteric inhibitor, a mixed inhibitor, or an irreversible inhibitor. 
     
     
         27 . The method of any one of the  claims 16  or  23 - 26 , wherein the PDE inhibitor comprises comprises ARL67156, diadenosine 5′,5″-boranopolyphosphonate, adenosine 5′-(α-borano)-β,γ-methylene triphosphate, adenosine 5′-(γ-thio)-α,β-methylene triphosphate, an oxadiazole derivative, a biscoumarine derivative, reactive blue 2, suramin, a quinazoline-4-piperidine-4-ethylsulfamide derivative, a thioacetamide derivative, PSB-POM1412-(3H-imidazo[4,5-b]pyridin-2-ylthio)-N-(3,4-dimethoxyphenyl)acetamide or a derivative, analog, or salt thereof; 2-(6-Amino-9H-purin-8-ylthio)-N-(3,4-dimethoxyphenyl)-acetamide, or a salt thereof; N-(3,4-Dimethoxyphenyl)-2-(5-methoxy-3H-imidazo[4,5-b]-pyridin-2-ylthio)acetamide or a salt thereof; 2-(1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl sulfamide or a salt thereof; ((1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl)methyl)sulfamide or a salt thereof; or SK4A (SAT0037) or a derivative or salt thereof. 
     
     
         28 . The method of one of the  claims 16  or  23 - 26 , wherein the PDE inhibitor comprises Compound 1, Compound 2, Compound 3, or a derivative, analog, or salt thereof. 
     
     
         29 . The method of  claim 16 , wherein the subject has been administered an immunogenic cell death (ICD) inducer prior to or simultaneously with the inhibitor of a 2′3′-cGAMP degradation polypeptide. 
     
     
         30 . The method of any one of the  claims 16 - 29 , wherein the inhibitor of a 2′3′-cGAMP degradation polypeptide is administered to the subject at a therapeutically effective amount. 
     
     
         31 . The method of  claim 30 , wherein the therapeutically effective amount of the inhibitor of a 2′3′-cGAMP degradation polypeptide selectively inhibits hydrolysis of 2′3′-cGAMP but not ATP hydrolysis in the 2′3′-cGAMP degradation polypeptide. 
     
     
         32 . The method of any one of the  claims 16 - 31 , wherein the subject is diagnosed with cancer.